Clonal Hematopoiesis and Incident Heart Failure With Preserved Ejection Fraction

Key Points Question Are clonal hematopoiesis of indeterminate potential (CHIP) or certain CHIP driver genes associated with a specific heart failure (HF) subtype? Findings In this cohort study of 2 racially diverse cohorts collectively including 8090 participants, TET2 CHIP was independently associated with a 2.4-fold higher risk of incident HF with preserved ejection fraction. By contrast, there were no significant associations of CHIP with incident HF with reduced ejection fraction. Meaning These results suggest that TET2 CHIP is a risk factor associated with incident HF with preserved ejection fraction.


eMethods Jackson Heart Study (JHS)
The JHS is a prospective cohort including 5,306 self-identified Black adults aged 21 to 84 years from Jackson, Mississippi, and the surrounding area.The JHS was designed as a community-based cohort to investigate risk factors for cardiovascular diseases in selfidentified Black U.S. citizens.Written informed consent was obtained from all study participants.The study protocol was approved by institutional review boards from the University of Mississippi Medical Center, Jackson State University, and Tougaloo College.
At enrolment (2000-2004) and subsequent study visits (2005-2009 and 2009-2013), participants underwent physical examination (including anthropometry and blood pressure measurements), donated blood samples, and provided detailed information on lifestyle, environment, and health history.We considered JHS participants for inclusion if they had whole-genome sequences available (N=3,404), which were generated as part of the NHLBI TOPMed program (National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine) in 3,404 consenting participants.Blood samples for whole-genome sequencing were collected at enrolment (n=3,284; 96.5%) or the second study visit (n=120; 3.5%).
Covariate data were obtained from each participant's corresponding study visit, except for smoking status, income, and education, which were only evaluated at baseline.Smoking was self-reported and categorized as (1) Current; Potential heart failure (HF) hospitalizations in the JHS were identified and adjudicated as described previously. 1 In brief, hospitalization data were obtained from hospital discharge lists and annual follow-up interviews.Self-reported data from the follow-up interviews were verified using data from hospital discharge lists.Hospital diagnoses based on ICD codes (International Classification of Diseases) were reviewed by trained personnel and adjudicated using the available clinical data (including clinical notes, laboratory tests, and imaging data).HF events were classified as HF with preserved ejection fraction (HFpEF; left ventricular ejection fraction ≥50%) or HF with reduced ejection fraction (HFrEF; left ventricular ejection fraction <50%) based on imaging data before and at the time of the initial HF hospitalization.JHS participants were followed for incident HF events from 2005 through 2016.

Women's Health Initiative (WHI)
The WHI is a prospective, multicenter study including 161,808 postmenopausal women recruited at 40 centers throughout the U.S. between 1993 and 1998.WHI participants enrolled in an observational study or at least one of three clinical trials (hormone therapy, calcium/vitamin D supplementation, or dietary modification).All WHI participants provided informed consent, and study protocols were approved by the appropriate local institutional review boards.
At enrolment, all included participants underwent physical examination (including anthropometry and blood pressure measurements) and provided information on medical history, health-related behaviors, and socio-economic characteristics.Race/ethnicity was ascertained using self-report, categorized as (1) American Indian or Alaskan Native; Of the 161,808 women in the original cohort, a sub-cohort of 44,174 women, were followed prospectively from baseline for hospitalized HF events.The WHI HF subcohort comprises a subset of participants randomized to the WHI hormone trial (n=27,347), as well as all Black and Hispanic participants from the observational study and other clinical trial components (n=16,827).Participants included in the WHI HF subcohort were followed for HF adjudication by yearly medical record abstraction of hospitalizations. 2 Trained adjudicators evaluated all confirmed HF hospitalizations, as well as patient-reported development of HF, angina, or other cardiovascular diseases, by reviewing clinical data (including clinical notes, laboratory tests, and imaging data) for evidence of HF.HF events were classified as HFpEF (left ventricular ejection fraction ≥50%) or HFrEF (left ventricular ejection fraction <50%) based on imaging data before and at the time of the initial HF hospitalization.WHI participants were followed for incident HF events from enrolment through 2022.
A subsample of unrelated WHI participants aged 50-79 years at blood draw had available CHIP calls from whole-genome sequences through the NHLBI TOPMed program (n=11,010; January 2020).Participants included in the WHI TOPMed sample were selected from a nested case-control study of incident stroke and venous thromboembolism.A subset of 3,643 WHI participants included in the current CHIP-HF analysis had available C-reactive protein measurements at the baseline exam, including 2,705 measured at the University of Minnesota (Modular P, Roche Diagnostics) and 938 at the University of Vermont (BN II, Dade Behring).
All multivariable-adjusted WHI models included inverse probability weights to account for inclusion in the TOPMed cohort as well as inclusion in the WHI HF cohort to allow inference to the sampling frame from which the participants was drawn, a process that decreases parameter bias.and stroke.CAD and diabetes mellitus were incorporated as time-varying covariates using the tmerge() function in R. JHS models were further adjusted for sex, while WHI models were further adjusted for race/ethnicity and inverse probability weights for inclusion in the TOPMed and HF adjudication cohorts.Any HF was defined as a composite outcome including HFpEF, HFrEF, and HF with unknown ejection fraction (HFuEF).
Effect estimates from both cohorts were meta-analyzed using fixed effects.Follow-up in the WHI was truncated at 22 years due to deviations from proportional hazards.Follow-up occurred over a median of 12.0 (IQR: 11.0-12.0)years in the JHS and 15.Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were calculated using Cox proportional hazards models adjusted for age at blood draw, income, education, smoking, body mass index, systolic blood draw, antihypertensive medication use, prevalent diabetes mellitus, and stroke.JHS models were further adjusted for sex, while WHI models were further adjusted for race/ethnicity and inverse probability weights for inclusion in the TOPMed and HF adjudication cohorts.Any HF was defined as a composite outcome including HFpEF, HFrEF, and HF with unknown ejection fraction (HFuEF).Effect estimates from both cohorts were meta-analyzed using fixed effects.Follow-up in the WHI was truncated at 22 years due to deviations from proportional hazards.There were a total of 2,826 JHS and 4,941 WHI participants without prevalent CAD at blood draw.Follow-up occurred over a median (IQR) of 12.0 (11.2-12.0)years in the JHS and 15.5 (9.diabetes mellitus, and stroke.JHS models were further adjusted for sex, while WHI models were further adjusted for race/ethnicity and inverse probability weights for inclusion in the TOPMed and HF adjudication cohorts.Any HF was defined as a composite outcome including HFpEF, HFrEF, and HF with unknown ejection fraction (HFuEF).Effect estimates from both cohorts were meta-analyzed using fixed effects.Follow-up in the WHI was truncated at 22 years due to deviations from proportional hazards.There were a total of 717 JHS and Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were calculated using Cox proportional hazards models adjusted for age at blood draw, income, education, smoking, body mass index, systolic blood draw, antihypertensive medication use, prevalent diabetes mellitus, coronary artery disease, and stroke.JHS models were further adjusted for sex, while WHI models were further adjusted for race/ethnicity and

( 2 )
Previous; (3) Never; or (4) Missing.Income categories were assigned based on family income and size and were adjusted for year of data collection to account for inflation, with (1) Less than the poverty level; (2) Lower-middle (1 to 1.5 times the poverty level); (3) Upper-middle (1.5 to 3.5 times the poverty level); (4) Affluent (>3.5 times the poverty level); and (5) Missing as the different categories.Education was incorporated as a four-category variable, with (1) Less than high school; (2) High school (or General Educational Development test) graduate; (3); Attended vocational school, trade school, or college; and (4) Missing as the different categories.

Multivariable-adjusted associations of clonal hematopoiesis of indeterminate potential (CHIP) and gene-specific CHIP subtypes with incident HF with preserved and reduced ejection fraction (HFpEF and HFrEF) using models incorporating coronary artery disease (CAD) and diabetes as time-varying covariates.
at blood draw, income, education, smoking, body mass index, systolic blood draw, antihypertensive medication use, CAD, diabetes mellitus, © 2024 Schuermans A et al.JAMA Network Open.

Multivariable-adjusted associations of clonal hematopoiesis of indeterminate potential (CHIP) and gene-specific CHIP subtypes with incident HF with preserved and reduced ejection fraction (HFpEF and HFrEF) in participants ≥65 years.
WHI models were further adjusted for race/ethnicity and inverse probability weights for inclusion in the TOPMed and HF adjudication cohorts.Any HF was defined as a composite outcome including HFpEF, HFrEF, and HF with unknown ejection fraction (HFuEF).Effect estimates from both cohorts were meta-analyzed using fixed effects.Follow-up in the WHI was truncated at 22 years due to deviations from diabetes mellitus, stroke, CHIP/gene-specific CHIP subtype, and age category (<65 vs. ≥65 years).JHS models were further adjusted for sex, © 2024 Schuermans A et al.JAMA Network Open.while

Multivariable-adjusted models testing the interaction between clonal hematopoiesis of indeterminate potential (CHIP) and age category (<65 vs. ≥65 years) on risk of incident HF with preserved and reduced ejection fraction (HFpEF and HFrEF).
P-values were calculated using Cox proportional hazards models adjusted for age at blood draw, income, education, smoking, body mass index, systolic blood draw, antihypertensive medication use, prevalent CAD, prevalent diabetes mellitus, and stroke.JHS models were further adjusted for sex, while WHI models were further adjusted for race/ethnicity and inverse probability weights for inclusion in the TOPMed and HF © 2024 Schuermans A et al.JAMA Network Open.adjudication cohorts.Any HF was defined as a composite outcome including HFpEF, HFrEF, and HF with unknown ejection fraction (HFuEF).Effect estimates from both cohorts were meta-analyzed using fixed effects.Follow-up in the WHI was truncated at 22 years due to deviations from proportional hazards.